Iodophors are well known germicidal agents comprising the combination of pharmaceutically acceptable, elemental iodine with an organic carrier selected from the group comprising, inter alia, povidone and cationic, anionic and non-ionic detergents.
Commercially available iodophor pharmaceutical preparations often have an inherent limitation of a sharp fall in titratable iodine content with subsequent loss in germicidal potency in storage. While many methods have been devised to obtain a substantially pure, stable iodophor product, products hitherto known in the art comprise variable quantities of iodides, which act to dissolve unreacted elemental iodine and serve as a catalyst for further autodegradation of the iodophor compound. This degradation of the iodophor compound and loss in titratable iodine content results in a lowered potency of pharmaceutical dosage forms containing these compounds and thereby limits the use of these agents for germicidal use.
It is known that when a iodophor compound is dissolved in aqueous or hydro-organic solvent, the level of titratable iodine will gradually decrease in the course of time, and that there will be an increase in the acidity of the iodophor solution. This lowering in titratable iodine content is the result of the well known reaction whereby the titratable iodine in aqueous solution reacts with hydrogen ions to form hydriodic acid which is a source of iodide ions. Thus, there is a catalytic conversion of available germicidal iodine to iodide ion over the course of time, resulting in a loss of germicidal potency as well as an increase in the solubilization of elemental iodine in its free form, thereby increasing the potential for irritation and toxicity.
While the loss of germicidal potency with time through the conversion of titratable iodine to iodide may be compensated by adding an excess of the iodophor compound at the time of manufacture of the pharmaceutical preparation, so as to constantly maintain a high level of titratable active germicidal iodine, this practice is costly as well as inherently contributory to a further increase of dissolved unreacted or loosely-bound elemental iodine in the solution, which contributes to possible noxious toxic responses.
Since in solution the iodophor complexed iodine, exerting microbicidal action, is in dynamic equilibrium with ionic iodine species, removal of one or more of the iodine species results in a reaction to restore said equilibrium. An extracting solvent removes or consumes iodine from the iodophor solution in a manner similar to that of a microbial and organic load during desinfecting use of the iodophor solution. The amount of iodine available for germicidal action in an iodophor preparation therefore is the amount of free iodine in equilibrium in the solution at the time of use. Such free or equilibrium iodine content represents the germicidal potency of the preparation, but not the total iodine content titrated for the preparation nor the apparent distribution of the iodine species. Although iodophor solutions have been assayed in the art for available or titratable iodine, it is the free or equilibrium iodine which is the particular form of iodine present in the iodophor solution that is instantly available to exert microbicidal action. This form of iodine differs from titratable iodine and the other iodine species present in the iodophor solution. Therefore, the equilibrium iodine content of an iodophor solution is to be distinguished from its titratable iodine content.
The titratable iodine content of an iodophor preparation includes the iodine reservoir of the iodophor preparation (povidone iodine), as well as the equilibrium iodine in solution:Titratable iodine=Reservoir Iodine+Equilibrium Iodine
However, it is the equilibrium iodine alone that exerts the microbicidal action of the preparation at any given moment. The portion of the titratable iodine content remaining after subtracting the amount of equilibrium iodine present, serves as the iodine reservoir to generate new equilibrium iodine in solution as it is consumed by the microbial and bio-organic load in the course of microbicidal activity, but does not exert such germicidal action by itself.
Povidone-iodine (polyvinylpyrrolidone-iodine or PVP-I) of pharmaceutical grade is the raw material used in the preparation of PVP-I containing formulations. Povidone-iodine is a complex of iodine with povidone. It contains not less than 9.0% by weight, and not more than 12% by weight of available iodine (titratable iodine) calculated on a dry basis.
Iodophor solutions, notably povidone-iodine, have been packaged for medicinal use, e.g. in soft plastic material bottles or containers which can be used for various medicinal purposes, e.g. douching. However, a problem that has been encountered with such-packaged iodophor solutions, is that elemental iodine (equilibrium iodine) has leached into and even through the packaging material. This has resulted in a loss of active iodine and in a decrease in stability of the iodophor solution contained within the packaging, and has also made it difficult to handle such packaging since elemental iodine which has leached there through causes staining and irritation if touched. Elemental iodine not only reacts with the packaging material but also with other reactive ingredients, e.g. unsaturated compounds, of the iodophor preparation resulting in a loss of stability.
U.S. Pat. No. 4,113,857 discloses that when an amount of from 0.005 percent to 1.0 percent by weight of iodate ion is added to a selected quantity of povidone-iodine at the time of its manufacture, there is obtained a polymeric iodophor compound that is uniquely free of iodide ion content and exhibits a preferred stability in aqueous solution, so that the fall in the amount of titratable iodine on aging is greatly reduced whereby no excess quantity of iodophor is necessary in the manufacture of pharmaceutical preparations employing said iodophor product.
U.S. Pat. No. 4,996,048 discloses a method to minimize loss of iodine from an iodophor solution, notably polyvinylpyrrolidone iodophor, which is stored within a packaging, by providing a certain minimal level of additional iodide, in addition to the iodophor solution, which prevents or minimizes leaching of. iodine. through the- packaging itself. The separate introduction of additional iodide, above and apart from the iodide already present in the noted iodophor solution, reduces the leaching of any elemental iodine from the iodophor solution through the packaging.
EP 0526695 discloses storage stable PVP-I solutions useful for ophthalmic preparations containing an alkanizing agent, which however have to be packaged in glass bottles. Glass bottles are disadvantageous with regard to easy breaking and causing dangerous splinters.
EP 0639373 discloses particulate, especially liposomal, preparations for the external application of agents with antiseptic and/or wound healing promoting properties. The preparations are specifically applied to wounds, skin, mucous membranes and mucosa-like unkeratinized epithelial tissues of humans and animals. The use of antiseptics such as povidone iodine is disclosed. Liposomes are highly suited as carriers for antiseptic agents, especially for povidone iodine, and for agents promoting the healing of wounds and provide an extended and topical activity at the desired locus of action by interaction with cell surfaces. However, the issue of stability is not addressed.
Liposomes are well-known drug or compound carriers and thus the application of medicaments in liposomal- form has been the subject of investigation for quite some time. An overview concerning the administration of compounds in liposomal form to the skin is provided by the review Targeted delivery to the pilosebaceous unit via liposomes (Lauer, A. C. et al. (1996), Advanced Drug Delivery Reviews, 18, 311-324). This review describes the physical-chemical characterisation of liposomal preparations and their therapeutic applications for the treatment of the pilosebaceous unit. Compounds that have been investigated for delivery by liposomes include e.g. anti-cancer agents, peptides, enzymes, anti-asthmatic and anti-allergic compounds and, as mentioned above, also antibiotics.
Lately it has been found that liposomal antiseptic preparations of PVP-I can be used for the treatment of diseases of the upper and lower respiratory tract, as disclosed in WO 99/60998' and PCT/EP 99/03681. Such liposomal preparations can be lyophilized. However, the storage stability of the preparations is not addressed.
Further yet unpublished work of the applicant even revealed that these liposomal antiseptic preparations can additionally be used for the treatment of herpes, acne and other infective diseases of the skin.
There is still a need of storage stable iodophor containing preparations which do not necessarily need the addition of special stabilizers like iodide salts, iodate salts or alkanizing agents and can he stored for years. e.g. two years or even longer, in plastic material bottles and containers or even in paper or cardboard packages, without encountering the above-discussed leaching problems, and without having to use glass as a packaging material.